Alzheimer's Disease (AD) is a progressive, neurodegenerative disease characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotionally stability. AD is a common cause of dementia in humans and a leading cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major public health problem throughout the world. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available and the disease is currently considered among experts to be incurable.
The histopathological manifestations of AD are characteristic lesions known as amyloid (or senile) plaques and neurofibrillar tangles that are found in the regions of the brain associated with memory, reasoning and cognition. Similar alterations are observed in patients with Trisomy 21 (Down's syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type.
The major constituent of amyloid plaques is amyloid β protein. Amyloid β protein is derived from the proteolytic cleavage of amyloid precursor protein (APP). Processing of APP to amyloid D protein and other APP fragments is governed by a group of enzymes known as secretases. One type of secretase, γ-secretase, is responsible for the protein cleavage that produces amyloid β protein. Compounds that inhibit either β or γ secretase activity, either directly or indirectly would reduce the production of amyloid β protein resulting in the treatment or prevention of disorders associated with amyloid β protein. Thus there is a continuing need for compounds that inhibit amyloid β protein production. The present invention meets this and related needs by providing a family of novel compounds and related methods of use.